Approximately 7% of Americans report use of dietary botanical supplements (Ervin, Wright, and Reed-Gillette, 2004). These supplements are used not only as presumed preventatives, but also as treatments of such diverse diseases as depression and viral infections. Despite the extensive use of these supplements, scientific studies to understand the biological properties of the compounds present in these plant extracts are limited and efficacy of many of the supplements is unclear. The Iowa Botanical Supplement Research Center has focused on investigations of the inflammatory, immune and anti-viral properties of extracts from two of the most extensively used botanicals, Echinacea and Hypericum (St. John's Wort). This project of the current renewal is an extension and expansion of the anti-viral studies. During our initial round of funding, we identified a number of anti-viral activities against the pathogen human immunodeficiency virus (HIV-1). In Aim 1, we propose to continue our identification of Echinacea and Hypericum anti-HIV activities and explore recent observations that extracts from Prunella species also contain anti-viral activities. Using a bioassay driven approach, constituents responsible for the anti-HIV activity will be identified. Once those constituents are identified and verified, the mechanism of action of the constituents will be investigated. In Aim 2, the breadth of the anti-viral activities in the extracts will be explored using important human respiratory viruses and persistent viruses. Finally, in Aim 3 correlative structural studies will be performed on two important groups of plant polyphenolic compounds, procyanidins and caffeic acid derivatives, to understand the relationship between their anti-oxidant activity and their anti-viral activity. These anti-oxidant compounds have been selected for study since they are principal anti-oxidant components in Echinacea, Hypericum and Prunella and recent studies in our labs and other indicate that they have important anti-viral activities. In addition, the ability of procyanidins and caffeic acid derivatives to enhance and/or synergize with the anti-viral activities of other plant constituents will be determined. In total, this study will determine if important anti-viral activities are indeed present within these botanicals. Additionally/our findings may serve as a basis for using botanical extracts and/or constituents for new, low-cost treatments for important human viral infections.